Pain whether acute or chronic, may result from actual damage to body tissue, for example in general medical illnesses, arthritis, cancer, neuropathies, and perioperative conditions. Pain may also be associated with medical disorders without a known cause, such as migraine and psychosomatic illness.
Acute pain usually remits on resolution of the injury. Acute pain is typically sensitive to blockade by administration of opioids, but opioids typically have a relatively short duration of action as well as undesirable side effects.
Chronic pain may be defined as pain having a duration of 3 months or more. Chronic pain may be associated with tissue damage, and may be continuous or episodic. Like postoperative pain, chronic pain may result from excessive nociceptive stimulation as in arthritis, but often originates from neuropathy or deafferentation, inflammation and psychogenesis.
Chronic pain is often refractory to specific or routine remedies, although some therapeutic agents may have mild to moderate efficacy. Even if treated with some efficacy, chronic pain may be associated with depression, insomnia, preoccupation, disablement, with the attendant economic costs to society.
Pain responses are essential for the protection of the body from further tissue injury. Pain can become pathological with exaggerated responses to nociceptive (hyperalgesia) or non-noxious sensory stimuli (allodynia). Both forms of sensitization occur at many levels of the nervous system, including primary nociceptors, dorsal and trigeminal root cell bodies, dorsal horn interneurons, spinothalamic neurons, brainstem neurons, and various forebrain neurons. Potentially, there are accordingly a very large number of targets for analgesic drugs. The targets include sodium and calcium ion channels and receptors for agents that modulate the appreciation and reaction to pain. The presynaptic and postsynaptic receptors involved in pain transmission include sites of interaction for opioids, cannabinoids, prostaglandins, serotonin (5-HT), norepinephrine, purines, nicotine, glutamate (AMPA and NMDA receptor subtypes), as well as neutral amino acids such as GABA and glycine.
Medications routinely used for acute and chronic pain therapy are derived from several pharmacologically distinct classes: opioids, nonsteroidal antiinflammatory drugs (NSAIDs), anticonvulsants and antimigraine drugs (5-HT receptor agonists and ergot derivatives). Morphine, representing a standard analgesic of reference, belongs to the opioid class of drugs that act on the central nervous system. The actions of NSAIDs and anti-migraine drugs are primarily on peripheral tissues.
Many medications belonging to the opioid and NSAID families are efficacious against acute pain caused by excessive nociceptive stimulation. There are, however, major difficulties associated with the use of these drugs. For example, the duration of most drugs in these classes is short, requiring repeated dosing. Dangerous side effects are associated with each class. Opioids, although generally much more effective analgesics than NSAIDs, produce addiction and respiratory depression, a life threatening side effect. Therapeutic use of NSAIDs is associated with significant gastrointestinal bleeding and renal damage.
Medications belonging to the antimigraine family are efficacious in the acute treatment of headache of unknown pathophysiology. However, 5-HT agonists and ergot derivatives produce highly variable analgesic responses, both among and within individual migraine patients. The large variation in the responses to these drugs and their appreciable side effects (such as nausea and vomiting) may be attributable to their complex pharmacology.
Many opioids and NSAIDs have little or no activity against chronic pain. Some opioids may relieve chronic pain of neuropathic and psychogenic origin, but generally only at doses that have unacceptable side effects.
In treating chronic pain, medical practitioners may resort to antidepressant agents, such as agents belonging to the tricyclic class (e.g., amitryptyline) to reduce neuropathic and psychogenic pain of weak or moderate intensity. Other medications such as anxiolytics, anticonvulsants (e.g., gabapentin), sodium channel blockers (e.g., lidocaine) or glucocorticoids, may also be prescribed alone or in combination with opioids and nonopioid analgesics. In addition to limited efficacy of the available analgesics, these approaches suffer from the fact that their long-term utilization is accompanied by secondary, undesirable effects. For example, utilization of opioids is associated with problems of tolerance and dependence, NSAIDs have digestive tract toxicity, and tricyclic antidepressants may produce hypotension, sedation and weight gain.
Exogenous application of biological amino acids is known to have a very wide variety of biological effects (see for example Beyer, Banes, Gomora, and Komisaruk, Pharmacology, Biochemistry & Behaviour 29: 73-78, 1988). Isovaline is known as a substituent (U.S. Pat. No. 5,726,200), subunit (WO 2005/058957), or excipient (U.S. Pat. No. 6,136,294) in various medicaments. Isovaline has for example been used in flavouring of zinc medicaments (U.S. Pat. No. 5,897,891). For these and other purposes a number of synthetic routes are available to produce isovaline, including stereo-specific synthetic approaches (see Mutter, et al., Stereoselective Synthesis Of Isovaline (IVA) And IVA-Containing Dipeptides For Use In Peptide Synthesis; Tetrahedron Letters; 1988; vol. 44, p. 4793). Isovaline (2-Amino-2-methylbutanoic acid) is represented in base form by the formula (I):

The racemate, R, and S enantiomers of isovaline are respectively referred to herein as compound (Ia), (Ib), and (Ic). The CAS Registry numbers for isovaline are: DL-isovaline [464-58-7]; L-Isovaline [595-39-1]; D-Isovaline [595-40-4]. Isovaline is not incorporated into mammalian protein. Isovaline has been found in meteoric fragments.